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Gene Review

SLC9A3  -  solute carrier family 9, subfamily A (NHE3...

Homo sapiens

Synonyms: NHE-3, NHE3, Na(+)/H(+) exchanger 3, Sodium/hydrogen exchanger 3, Solute carrier family 9 member 3
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Disease relevance of SLC9A3

  • Expression levels of the cystic fibrosis transmembrane regulator (CFTR) (Cl- channel), SLC26A3 (Cl-/HCO exchanger) and SLC9A3 (Na+/H+ exchanger) mRNAs were measured by real-time quantitative RT-PCR in peroperative colonic samples from controls (n = 4) and patients with ulcerative colitis (n = 10) [1].
  • OBJECTIVES: The objectives of this study were to identify polymorphic variants within the gene coding for the sodium/hydrogen exchanger type 3 (NHE3) and to examine their relationship with hypertension and biochemical indices of sodium balance [2].
  • These albumin-induced increases in expression and activity of NHE3 in PTC suggest a possible mechanism for Na+ retention in response to proteinuria [3].
  • Chronic metabolic acidosis markedly increases HCO3- absorptive capacity of MTAL, by stimulating at least the synthesis of apical NHE-3 protein, as in the proximal tubule [4].
  • The paradoxical increase in HCO3- absorptive capacity of MTAL observed in the model of chronic NaHCO3-load alkalosis should be due to other factors overcoming the inhibitory effect of alkalosis on NHE-3 [4].

Psychiatry related information on SLC9A3

  • OBJECTIVES: To further explore the possible role of this exchanger for the control of breathing, we examined the individual relationship between brainstem NHE3 abundance and ventilation in rabbits during wakefulness [5].
  • The protein abundance of mTAL BSC1, NHE3, and Na+ pump increased significantly in young but remained unchanged in 7-month-old rats subjected to water deprivation [6].

High impact information on SLC9A3

  • Moreover, TNF, but not LIGHT, inhibited Na(+) absorption due to TNF-induced internalization of the brush border Na(+)/H(+) exchanger NHE3 [7].
  • Using isoform-specific primers, mRNA transcripts of the Na(+)/H(+) exchangers NHE1, NHE2, and NHE3 were detected by RT-PCR, and identities were confirmed by sequencing [8].
  • Functional NHE1 and NHE3 activities were identified at the basolateral and apical membranes, respectively [8].
  • 10(-7) M and 10(-8) M hydrocortisone increased NHE3 activity, and in their presence, acid incubation further increased NHE3 activity [9].
  • In addition, hypertonicity increased total cellular and plasma membrane NHE3 protein abundance twofold, with only a small increase in NHE3 mRNA abundance [10].

Chemical compound and disease context of SLC9A3

  • Conclusion: These results suggest that exposure of PTCs to high glucose concentrations promotes osmolality mediated cell hypertrophy and increased tubular albumin reabsorption linked to an increase in NHE-3 expression [11].
  • Acute CPA-induced control of NHE3 was blocked by antagonists of A1 adenosine receptors and inhibition of phospholipase C, pretreatment with BAPTA-AM (chelator of cellular calcium), and exposure to pertussis toxin [12].
  • The nonreceptor tyrosine kinase, c-Src, plays a key role in regulation of NHE3 by acidosis in the proximal tubule, and in signaling effects of angiotensin II in vascular smooth muscle [13].
  • NHE3 is acutely up- and downregulated in response to some G protein-linked receptors, tyrosine kinase receptors, and protein kinases when studied in intact ileum, when stably expressed in PS120 fibroblasts, and in the few studies reported in the human colon cancer cell line Caco-2 [14].
  • Levels of urinary NHE3 normalized to urinary creatinine level were increased in patients with prerenal azotemia and 6 times as much in patients with ATN, without overlap (ATN, 0.78 +/- 0.36; prerenal azotemia, 0.12 +/- 0.08; P < 0.001) [15].

Biological context of SLC9A3


Anatomical context of SLC9A3


Associations of SLC9A3 with chemical compounds

  • At least two luminal transporters mediate HCO(3)(-) salvage, the Na(+)/H(+) exchanger (NHE3) and the Na(+)-HCO(3)(-) cotransport (NBC3) [23].
  • Forskolin and VIP inhibit pH(i) recovery (NHE3 function) from beta-alanine-induced intracellular acidification [21].
  • Using confocal microscopy with a novel antibody raised against the predicted extracellular NH2 terminus of human NHE3, we observed in nonpermeabilized cells that exposure of PTC to albumin (0.1 and 1.0 mg/ml) increased NHE3 at the cell surface to 115.4 +/- 2.7% (P < 0.0005) and 122.4 +/- 3.7% (P < 0.0001) of control levels, respectively [3].
  • Moreover, there was an additional, equivalent increase (P < 0.05) in duodenal HCO(3)(-) output with 10(-3) M amiloride, which inhibited NHE3 [24].
  • SCFA increase intestinal Na absorption by induction of NHE3 in rat colon and human intestinal C2/bbe cells [25].

Physical interactions of SLC9A3

  • E3KARP binds an internal region within the NHE3 C-terminal cytoplasmic tail, defining a new mode of PDZ domain interaction [18].
  • In a previous work, we show that CFTR interacts with NHE3 to regulate its activity (Ahn, W., Kim, K. W., Lee, J. A., Kim, J. Y., Choi, J. Y., Moe, O. M., Milgram, S. L., Muallem, S., and Lee, M. G. (2001) J. Biol. Chem. 276, 17236-17243) [23].
  • We now show that NHE3 directly binds ezrin at a site in its C terminus between aa 475-589, which is separate from the PSD95/dlg/zonular occludens-1 (PDZ) interacting domain [17].
  • The intestinal and renal proximal tubule brush border (BB) Na+-H+ exchanger NHE3 binds to members of the NHERF (Na+-H+ exchanger regulatory factor) family [26].
  • Taken together, these findings indicate that a significant pool of NHE3 exists as a multimeric complex with megalin in the brush border of the proximal tubule [27].

Co-localisations of SLC9A3


Regulatory relationships of SLC9A3

  • NHERF-1/EBP50 was previously shown to regulate Na(+)/H(+)-exchanger 3 (NHE3) activities in OK cells [29].
  • Akt2 phosphorylates ezrin to trigger NHE3 translocation and activation [20].
  • In conclusion, we have shown that amino acid uptake via hPAT1 is inhibited by activators of the cAMP pathway indirectly through inhibition of NHE3 activity [21].
  • In addition, proximal duodenal mucosal HCO(3)(-) transport was measured in humans in vivo in response to luminal perfusion of graded doses of amiloride; 10(-5)--10(-4) M amiloride was used to inhibit NHE2 and 10(-3) M amiloride to inhibit NHE3 [24].
  • Our data indicate that IFN-gamma and TNF-alpha may repress the NHE3 promoter activity in C2BBe1 cells by PKA-mediated phosphorylation of Sp1 and Sp3 transcription factors [30].

Other interactions of SLC9A3

  • In intact epithelia, PAT1-mediated amino acid influx is reduced under conditions in which NHE3 is inactive [31].
  • The distributions of NHE3 and E3KARP were not affected by treatment with 8-bromo-cAMP [18].
  • We reported recently that this NHE3 translocation requires ezrin phosphorylation [20].
  • Pharmacological Akt inhibition or Akt2 knockdown also prevented NHE3 translocation and activation after initiation of Na(+)-glucose cotransport, confirming the functional role of Akt2 [20].
  • The complementary DNA (cDNA) sequences of NHE1 to NHE3 and NHE5 are known in humans [32].

Analytical, diagnostic and therapeutic context of SLC9A3


  1. Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis. Lohi, H., Mäkelä, S., Pulkkinen, K., Höglund, P., Karjalainen-Lindsberg, M.L., Puolakkainen, P., Kere, J. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  2. Molecular variants of the sodium/hydrogen exchanger type 3 gene and essential hypertension. Zhu, H., Sagnella, G.A., Dong, Y., Miller, M.A., Onipinla, A., Markandu, N.D., MacGregor, G.A. J. Hypertens. (2004) [Pubmed]
  3. Effects of pathophysiological concentrations of albumin on NHE3 activity and cell proliferation in primary cultures of human proximal tubule cells. Lee, E.M., Pollock, C.A., Drumm, K., Barden, J.A., Poronnik, P. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  4. H+ and HCO3- transporters in the medullary thick ascending limb of the kidney: molecular mechanisms, function and regulation. Paillard, M. Kidney Int. Suppl. (1998) [Pubmed]
  5. Sodium/Proton exchanger 3 in the medulla oblongata and set point of breathing control. Wiemann, M., Frede, S., Bingmann, D., Kiwull, P., Kiwull-Schöne, H. Am. J. Respir. Crit. Care Med. (2005) [Pubmed]
  6. Resistance of mTAL Na+-dependent transporters and collecting duct aquaporins to dehydration in 7-month-old rats. Amlal, H., Wilke, C. Kidney Int. (2003) [Pubmed]
  7. Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. Clayburgh, D.R., Musch, M.W., Leitges, M., Fu, Y.X., Turner, J.R. J. Clin. Invest. (2006) [Pubmed]
  8. H(+)/solute-induced intracellular acidification leads to selective activation of apical Na(+)/H(+) exchange in human intestinal epithelial cells. Thwaites, D.T., Ford, D., Glanville, M., Simmons, N.L. J. Clin. Invest. (1999) [Pubmed]
  9. Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3). Ambühl, P.M., Yang, X., Peng, Y., Preisig, P.A., Moe, O.W., Alpern, R.J. J. Clin. Invest. (1999) [Pubmed]
  10. Chronic hyperosmolality increases NHE3 activity in OKP cells. Ambühl, P., Amemiya, M., Preisig, P.A., Moe, O.W., Alpern, R.J. J. Clin. Invest. (1998) [Pubmed]
  11. Albumin and glucose effects on cell growth parameters, albumin uptake and Na(+)/H(+)-exchanger Isoform 3 in OK cells. Drumm, K., Lee, E., Stanners, S., Gassner, B., Gekle, M., Poronnik, P., Pollock, C. Cell. Physiol. Biochem. (2003) [Pubmed]
  12. Bimodal acute effects of A1 adenosine receptor activation on Na+/H+ exchanger 3 in opossum kidney cells. Di Sole, F., Cerull, R., Petzke, S., Casavola, V., Burckhardt, G., Helmle-Kolb, C. J. Am. Soc. Nephrol. (2003) [Pubmed]
  13. Dominant negative c-Src inhibits angiotensin II induced activation of NHE3 in OKP cells. Tsuganezawa, H., Preisig, P.A., Alpern, R.J. Kidney Int. (1998) [Pubmed]
  14. Short-term regulation of NHE3 by EGF and protein kinase C but not protein kinase A involves vesicle trafficking in epithelial cells and fibroblasts. Donowitz, M., Janecki, A., Akhter, S., Cavet, M.E., Sanchez, F., Lamprecht, G., Zizak, M., Kwon, W.L., Khurana, S., Yun, C.H., Tse, C.M. Ann. N. Y. Acad. Sci. (2000) [Pubmed]
  15. Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF. du Cheyron, D., Daubin, C., Poggioli, J., Ramakers, M., Houillier, P., Charbonneau, P., Paillard, M. Am. J. Kidney Dis. (2003) [Pubmed]
  16. Ezrin regulates NHE3 translocation and activation after Na+-glucose cotransport. Zhao, H., Shiue, H., Palkon, S., Wang, Y., Cullinan, P., Burkhardt, J.K., Musch, M.W., Chang, E.B., Turner, J.R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  17. The NHE3 juxtamembrane cytoplasmic domain directly binds ezrin: dual role in NHE3 trafficking and mobility in the brush border. Cha, B., Tse, M., Yun, C., Kovbasnjuk, O., Mohan, S., Hubbard, A., Arpin, M., Donowitz, M. Mol. Biol. Cell (2006) [Pubmed]
  18. NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ezrin. Yun, C.H., Lamprecht, G., Forster, D.V., Sidor, A. J. Biol. Chem. (1998) [Pubmed]
  19. NHE3 serves as a molecular tool for cAMP-mediated regulation of receptor-mediated endocytosis. Gekle, M., Serrano, O.K., Drumm, K., Mildenberger, S., Freudinger, R., Gassner, B., Jansen, H.W., Christensen, E.I. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  20. Akt2 phosphorylates ezrin to trigger NHE3 translocation and activation. Shiue, H., Musch, M.W., Wang, Y., Chang, E.B., Turner, J.R. J. Biol. Chem. (2005) [Pubmed]
  21. Indirect regulation of the intestinal H+-coupled amino acid transporter hPAT1 (SLC36A1). Anderson, C.M., Thwaites, D.T. J. Cell. Physiol. (2005) [Pubmed]
  22. The role of NHERF-1 in the regulation of renal proximal tubule sodium-hydrogen exchanger 3 and sodium-dependent phosphate cotransporter 2a. Weinman, E.J., Cunningham, R., Wade, J.B., Shenolikar, S. J. Physiol. (Lond.) (2005) [Pubmed]
  23. The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3. Park, M., Ko, S.B., Choi, J.Y., Muallem, G., Thomas, P.J., Pushkin, A., Lee, M.S., Kim, J.Y., Lee, M.G., Muallem, S., Kurtz, I. J. Biol. Chem. (2002) [Pubmed]
  24. Human duodenal mucosal brush border Na(+)/H(+) exchangers NHE2 and NHE3 alter net bicarbonate movement. Repishti, M., Hogan, D.L., Pratha, V., Davydova, L., Donowitz, M., Tse, C.M., Isenberg, J.I. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  25. SCFA increase intestinal Na absorption by induction of NHE3 in rat colon and human intestinal C2/bbe cells. Musch, M.W., Bookstein, C., Xie, Y., Sellin, J.H., Chang, E.B. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  26. NHERF family and NHE3 regulation. Donowitz, M., Cha, B., Zachos, N.C., Brett, C.L., Sharma, A., Tse, C.M., Li, X. J. Physiol. (Lond.) (2005) [Pubmed]
  27. Specific association of megalin and the Na+/H+ exchanger isoform NHE3 in the proximal tubule. Biemesderfer, D., Nagy, T., DeGray, B., Aronson, P.S. J. Biol. Chem. (1999) [Pubmed]
  28. The epithelial sodium-hydrogen antiporter Na+/H+ exchanger 3 accumulates and is functional in recycling endosomes. D'Souza, S., Garcia-Cabado, A., Yu, F., Teter, K., Lukacs, G., Skorecki, K., Moore, H.P., Orlowski, J., Grinstein, S. J. Biol. Chem. (1998) [Pubmed]
  29. kappa Opioid receptor interacts with Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins. Huang, P., Steplock, D., Weinman, E.J., Hall, R.A., Ding, Z., Li, J., Wang, Y., Liu-Chen, L.Y. J. Biol. Chem. (2004) [Pubmed]
  30. IFN-{gamma} and TNF-{alpha} regulate human NHE3 gene expression by modulating the Sp family transcription factors in human intestinal epithelial cell line C2BBe1. Amin, M.R., Malakooti, J., Sandoval, R., Dudeja, P.K., Ramaswamy, K. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  31. H+/amino acid transporter 1 (PAT1) is the imino acid carrier: An intestinal nutrient/drug transporter in human and rat. Anderson, C.M., Grenade, D.S., Boll, M., Foltz, M., Wake, K.A., Kennedy, D.J., Munck, L.K., Miyauchi, S., Taylor, P.M., Campbell, F.C., Munck, B.G., Daniel, H., Ganapathy, V., Thwaites, D.T. Gastroenterology (2004) [Pubmed]
  32. Human Na+/H+ exchanger genes : identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease. Yu, H., Freedman, B.I., Rich, S.S., Bowden, D.W. Hypertension (2000) [Pubmed]
  33. Molecular cloning and functional analysis of the human Na(+)/H(+) exchanger NHE3 promoter. Malakooti, J., Memark, V.C., Dudeja, P.K., Ramaswamy, K. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  34. Intestinal distribution of human Na+/H+ exchanger isoforms NHE-1, NHE-2, and NHE-3 mRNA. Dudeja, P.K., Rao, D.D., Syed, I., Joshi, V., Dahdal, R.Y., Gardner, C., Risk, M.C., Schmidt, L., Bavishi, D., Kim, K.E., Harig, J.M., Goldstein, J.L., Layden, T.J., Ramaswamy, K. Am. J. Physiol. (1996) [Pubmed]
  35. The Na+/H+ exchanger gene family. Burckhardt, G., Di Sole, F., Helmle-Kolb, C. J. Nephrol. (2002) [Pubmed]
  36. Akt2, phosphatidylinositol 3-kinase, and PTEN are in lipid rafts of intestinal cells: role in absorption and differentiation. Li, X., Leu, S., Cheong, A., Zhang, H., Baibakov, B., Shih, C., Birnbaum, M.J., Donowitz, M. Gastroenterology (2004) [Pubmed]
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